N-disubstituted-amino t-hydroxy ketones



Patented Jan. 1, 1952 N-DISUBSTITUTED-AMINO T-HYDROXY KETONES Richard S.Wilder, Roslyn, and Daniel F. Herman,

Philadelphia, Pa., assignors to Publicker Industries Inc., Philadelphia,Pa., a corporation of Pennsylvania N Drawing. Application April 10, 1947,

- Serial No. 740,727

The present invention relates to new. com positions of matter. Moreparticularly 'it is concerned with novel N-disubstituted amino t-hydroxyketones and to a process for the preparation thereof, such compositionsbeing represented by the following structure:

wherein R and R are members of the group consisting of aliphatic groupscontaining one to three carbon atoms and may be connected to complete acyclohexyl ring and whereinlEt and R are members of the group consistingof aliphatic groups containing one to three carbon atoms and maybecombined to complete a cyclic radical of the group consistingof'morpholine and piperidene rings.

In accordance with the present inventionyit has been found thatt-hydroxy methyl ketones can be reacted with formaldehyde and an amineor salts thereof to produce compounds of the type set forth in theforegoing structural formula. The fact. that these compounds react toform the aforesaid N-disubstituted amino t-hydroxy ketones under theconditions herein set forth without major complicating side reactions issur-. prising, inasmuch as it is well known that tertiary alcoholsdehydrate with ease, particularly when heated in the presence of anamine salt. Moreover, it is well established that the presence of aketone group in the molecule greatly increases the ease of dehydrationof a tertiary alcohol, especially where there is the possibilityofforming a conjugated unsaturated system.- Typical examples of thisphenomenon are the dehydra tgon of diacetone'alcohol'to mesityl oxideand of aldol to crotonaldehyde, even under the mildest dehydratingconditions. Moreover, 2-methylbutan-2-ol-3-one is known to undergodimerization and give undesirable condensation products in the presenceof acidic catalysts. Because of these known facts, reactions of the typejust cited might normally be expected to occur under the conditionsemployed in carrying out the present invention and, accordingly, it isbelieved t-o'have' been entirely unpredictable that the, desiredN-disubstituted amino t-hydroxy ketones would be produced in excellentyields.

The new compounds of the present invention are conveniently prepared inyields as high as 90% of the value theoretically obtainable bycondensing a. suitable t-hydroxy methyl ketone with formaldehyde in thepresence of a secondary 20 Claims- (Cl. 260-247) amine or a suitableacid salt thereof, at temperatures of from about to 150 C. andpreferably at from about to C., in the presenc of agitation.

The proportion of reactants may bevaried; however, it is generallypreferable to employ approximately equimolecular quantities of t-hydroxy ketone, formaldehyde and amine salt. With a substantial excess offormaldehyde and amine salt over that theoretically required to reactwith the t-hydroxy ketone, i. e., of the order of 50% excess or more, ithas been found that a second substituted aminomethyl group is introduced into the molecule. It has further been found that when the freeamine is used in place of the amine salt, even in equimolecularquantities, the principal product is the di aminomethyl derivative. Thusfor examplausing 2-methylbi1tan-2-ol-3-o1ie and a molar excess offormaldehyde and diethylamine salt, the predominating reaction found tooccur is considered to be as follows:

. presence of a suitable inert solvent is preferable in order todiminish the possibility of the occurrence of undesirable sidereactions. After the reaction is completed, as may be evidenced by a,noticeable decrease in the odor of formaldehyde in the reaction mixture,the latter is subjected to distillation under reduced pressure and theN-disubstituted amino t-hydroxy ketone thus formed recovered. In theevent the acid salt of the amine is used the reaction mixture, after thereaction has been completed, is poured into a volume of water generally,approximately equal to the volume of the reaction mass and the result oras trioxane.

ing mixture is saturated with a suitable alkaline salt, such as forexample, potassium or sodium carbonates, whereby the freeN-disubstituted amino t-hydroxy ketone is liberated and generallycollects at the .surface .of the .mixture, usually in the form of anoil. The products thus obtained may then be separated in accordance withknown methods and further purified by any suitable means, such as forexample, by fractional distillation under reduced pressure.

The t-hydroxy ketones suitable for use in preparing the new compositionsof this invention may be selected from a wide range of compounds and itmay generally be said that any t-hydroxy ketone is operative in thepresent invention wherein the tertiary hydroxyl group is adjacent to thecarbonyl carbon atom. As examples of such Example II Amixture'ccnsisting of 163 parts of 3-methylpentan-3-ol-2-one, 142 partsof diethylamine hydrochloride, and 39.6, parts .of ,paraformaldehyde is.heated'for a' period fof'tfive hours on a lowing physical properties:B. P., 85-S9 C./8 mm.;

Analysis. Calculated carbon content of 4-methyl-1-diethy1aminohexan 4 ol3 one, 65.5%.; found, 65.60%. Calculated hydrogen content, l1.43%;found, 11.45%.

compounds there may be mentioned 2-methylbutan-2-ol-3-one,l-hydroxycyclohexyl methyl.

ketone, 3- (pi-phenyleth'yl) butan-3-ol-2-one, 3-

.benzylbutan-3-o1-2-one, 1 ,hydroxycyolopentyl .methyl pentan 3ol-2-one, 3-phenylbutan-3eole2-one,

3,5edimethylhexan-3-ol-2-one, and the like.

In carrying out the present invention theformaldehyde may be employed inthe form or a 35 to 40 aqueous solution; as paraforma-ldehyde, Secondaryamines suitable :for use in the present-invention are those whose saltsreadily hydrolize in water-and it is tobe strictly understood that'theexpressions secondary amine or secondary amine sal s appearing herein,are to be construed as referring only to amines havingthe aforesaidproperties. AS examples of such amines there :maybe -mentioneddieth-yla-mine. dimethylamine, diisopropyl amine, morpholinaxpiperidine,di-benzylamine,

phenylbenzylamine, methyl aniline,.or the"a'cid ally been foundpreferable to employ amines of the aforesaid types in the form of theirsalts. Likewise, it is to be understood that, inasmuch as it has beenfound that the reaction here involved is very general in nature, thepresent invention contemplates the utilization of any salts 5 of the.foregoing classes of-amines having. the above mentioned properties.

' The present invention .may be. .furtherlillustrated by the followingspecific examples.

Example I A mixture consisting of 132 parts of 2-methylbutan-2-ol-3-one,1 52 parts of 'diethylamine hydrochloride, and 39.6 parts ofparaformaldehyde is heated for five .hours on a steam bath withagitation. At the end of this period the resulting. viscous ambercoloredproduct is poured into .300 parts of water and themixturesaturated with potassium carbonate to salt out the free base,which is observed to rise to the top to form an upper layer.Distillation of this oil layer gives a good yield ofei-methyl-l-diethy1aminep.entan- 4-ol-3.-one, miscible with water in allproportions and having the 7 following properties: .13. P... 85-87 (3/10mm.; 11 1. 1581; (14 0.980.

Analysis..Calculated carbon content of 4-methyl-l-diethyl-aminopentan 4ol 3 one,-

64.18% found, 64.05%. Calculated hydrogen content, 11.22%; found,11.20%.

Example III A mixture consisting-of 191 parts of3,5-dimethylhexan-3vol-2-one, .1 42 parts. of diethylaminehydrochloride, and- .3.9.6;parts ;o.f".pa'ra formaldehydexis subjectedto the: same. ;reac-- tion conditions asset forth in Examples :IandlII.On completion: of I the reaction the: produ'ctiis isolated and distilledtogive a good yield of 4,6- dimethyl-l-diethylaminoheptan-4-ol-3-0nehaving the following physical properties: B. P. 105- 112 C./8 mm.; n1.4629; (14 0.947.

Analysis-Calculated carbon content of 4,6- dimethyl-lediethylaminoheptan4 ol 3,: one, 68.2 found, 68.12 Calculated .hydrogencontent,.1.1.78.%,;found, 11.40%.

Example JV .A mixture consisting of .44grams of .3-ethy-lpentan-3-ol-2-one, 41.5 parts of diethylamine hydrochloride, and 11.3 parts ofparaformaldehyde is heated with agitation for four hoursat SO-SOTC. .Atthe .endof this period thereaction mixture is diluted-with .LOOparts ofwater and the amineis liberated-by saturating .the resulting mixturewith potassium carbonate. 'The resulting oily layer i separated from:t-he reaction and fractionally'distilled';at. 10 .mm. vacuum. The4.-ethyl-'1-diethylam-inohexan4-01-3-'one has the following physicalproperties: .B. P. .80-83? 6/ '10. mm.; n 5, 1.45162 d4 0:953.

"Example 1V A mixture consisting of 18 parts of l-hydroxycyclohexylmethyl 'ketone, 15.4' parts of diethylamine hydrochloride and 3.3 partsof paraformaldehyde is heated'with agitation on a steam bath forthreeand one-half-hours. At the end of this period the'reaction mixture isdiluted with parts of water and thereafter "saturated with potassiumcarbonate. Distillation of ,the'oil layer thus obtained yields3-diethylamino-.-1-'(1-ihy droxycyclohexyl) -'lpropanone having the'following physical properties: B. P., 80-859/10 mm.; 11 1.4817; d40.996.

.. Example VI A mixture consisting of 2'7 parts .of 2:-methyl-.butan-2-ol-3-one, 10. parts .of paraformaldehyde, and 29 partsordiisopropylamine hydrochloride is. heated ona steam bath fora periodof eight and one-half hours. .At the end of .this period the resultingmixture is. diluted with ,partsof water and thereafter saturated withpotassium carbon-- ate. The -methyl-l-diisopropylaminopentan- 4-ol-3-onethus liberated ondistillation boilsat 80.87/10 mm.

" Example VII the following physical. properties: B.P., 115-120- jo m m;11;, 1.4761; (14, l.056.

Example VIII 1A mixture consisting of'jlOZ parts of2-methylbutan-2-ol-3-1one, 33 parts .paraformalde hyd e and 80.3 partsof diethylamine is agitated and heated at about 90 C. for four hours.The re acted mixture issubjected to vacuum distillationand a smallamount of 4-methyl-1-diethylaminopentan-i ol-t-one obtained. However,the principal product is 3-methyl-1,l-di-(diethyb am nomethyl)-butari-3-ol-2-one, boiling at 140 to 150 C. at mm. 1

, Example IX A mixture consisting of 102 parts of 2-methyl+butan-2-ol-3-one, 152 parts of 37% aqueous formaldehyde and 219 parts ofdiethylamine hydrochloride is agitated and heated at about 90 C. forfour and one-half hours. The mixture is thendiluted with an equal volumeof water and saturated with. potassium carbonate. The upper, organicliquid layer is separated and fractionally distilled under vacuum. Thechief product is 3-methyl-1,1-di-(diethylaminomethyl)-butan-3-ol-2-one,boiling at 140-147" C. at 10 Because of the fact thatthe new N-disubstituted amino t-hydroxy ketones of our invention possessthe unique combination of three reactive functional groups, thesecompounds may be utilized as intermediates for the preparation of a widevariety of valuable derivatives such as for example, coatingcompositions (as disclosed and covered by the claims of our copendingapplication U. S. Serial No. 759,725, filed July 8, 1947, now PatentNumber 2,540,153), pharmaceuticals, dyestuffs, and the like.

It is to be understood, of course, that the above examples areillustrative only and do not limit the scope of our invention. Otherreactants of the classes previously defined could be substituted forthose specifically employed in the examples and the reaction conditionscould be modified in numerous respects without materially afiecting theresults. In general it may be said that the use of any equivalents ormodifications of procedure, which would naturally occur to one skilledin the art, is included in the scope of our invention.

Our invention now having been described, what we claim is:

l. N-disubstituted amino-t-hydroxy ketones of the general formulawherein R and R are members of the group consisting of one to fourcarbon atom alkyl radicals and the one hydroxy cyclohexyl radical, and

wherein R 'and R are 'n'iexnbers of the: group consisting of alkylgroups containingone to three carbon atoms and may be combinedto.complete a cyclic radical of the group consisting'of morpholine andpiperidine rings. it 7 r 2. 4 methyl 1 diethylaminopentan-4-ol-3- one. i

3. 4,6 dimethyl 1 diethylaminoheptan ol-3-one. r r i r 4. 4 methyl ldiethylaminohexan 4-ol-3 one. 5. 4-methyl-1-morpholinopentan-4-ol-3-one.

6. 3 diethylamino-J-(1-hydroxycyclohexyl) l-propanone. u 7. A processfor the synthesis of aminohydroxy ketones which comprises reacting ahydroxy methylketone having the formula wherein R and R are members ofthe group consisting of one to four carbon atom alk'yl'radicals and theone hydroxy cyclohexyl radical with formaldehyde and a secondary aminehaving the formula ru e-R wherein R and R. are members of the groupconsisting of alkyl groups containing one to three carbon atoms andmaybe combined to complete a cyclic radical of the group consisting ofmorpholine and piperidene rings ata temperature not substantially above150 C.

' v 8. A process for the synthesis of aminohydroxy ketones whichcomprises reacting a hydroxy methyl ketone having the formula n s c-onlH t wherein R and R are members of the group consisting of one to fourcarbon atom alkyl radicals and the one hydroxy cyclohexyl radical withsubstantially equimolecular amounts of formaldehyde and a salt of asecondary amine having the formula R: Hl I-R wherein R and R are membersof the group consisting of alkyl groups containing one to three carbonatoms and may be combined to complete a cyclic radical of the groupconsisting of morpholine and piperidene ringsat a temperature notsubstantially above 150 C.

9.The process of claim '7 in which the reaction temperature is about-100 C.

10. The process of claim 8 in which the reaction temperature is about90-100 C.

11. A process for the synthesis of4-methyl-ldiethylaminopentan-4-ol-3-one which comprises reacting2methyl-butan-2-ol-3-one, formaldehyde, and diethylamine, insubstantially equi molecular amounts at a temperature not substantiallyabove C.

12. A process for the synthesis of 4,6dimethyll-diethylaminoheptan-4-01-3-one which comprises reacting3,5-dimethylhexan-3-ol-2-one, formaldehyde, and diethylamine, insubstantially equimolecular amounts at a temperature not substantiallyabove 150 C.

13. A process for the synthesis of 4-methyl-1-diethy1aminohexan-4-ol-3-one which comprises reacting 3emethy1pentan3blr2:-one, "formalde hyde, and *diethylamine, .ingsubstantiallyequimolecular: amounts ata temperature, not, substantially'above 150 C.

14. A process for the synthesis of 4-methyllmorpholinopentan-2'ol3,=onewhich comprises reacting 2-methylbutan-2-ol-3-one, formaldehydeyandra,morpholine salt, in substantially equimolecular amounts at atemperature not substantially: above, 150 C.

15. A process for the synthesis of3-diethylamino-1-'(lehydroxycyclohexyl) 1 propanone which 1 comprisesreacting 11-hydroxycyc1ohexyl methyl ketone, formaldehyde, anddiethylamine, in L substantially equi'molecular amounts at a temperaturenot substantially above 150 C.

16. A process'for the synthesis of -4-methyl-1-diethylaminopentan-i-ol-3-one which comprises reacting2-methyl-butan-2-o1-3-one, formaldehyde, and a hydrolzable salt ofdiethylamine, in substantially equimolecula'r'amounts at atemtperaturepofx-about 907100 0. for about 5 hours,

thereafter pouring. the reaction mixture into an exbessof water, andthereafter salting out the free -base.-

17. A process for the synthesis of 4,6 dimethyl-1-diethy1aminoheptan-4-0l-3 one which comprises reacting3,5-dimethylhexan-3-ol-2-one, formaldehyde, and a-hydrolyzab1e salt ofdiethylamine, in substantially equimolecular amounts- -a-t-a temperatureof about 90-100 C. forzabout hours, thereafter pouring the reactionmixture-intoan 'excess'of water, and thereafter salting out the freebase.

18. A process for the synthesis of '4-methy1-1-diethylaminochexan-kol-Zi-one which comprises reacting3-methylpentan-3ol-2-one, formaldehyde, and a hydrolyzable salt ofdiethylamine, in substantially equimolecular amounts at a temperature ofabout 90100 C. for about 5 hours, thereafter pouring the reactionmixture into an excess of water, and thereafter saiting out the freebase.

.19. A process for. the synthesis of 4-me't'hy1-1r morpholinopentan-2-o13+one which comprises reacting 2-methylbutan -2 ol-3-one, formaldehyde,and a hydrolyzable salt of diethylamine, in substantially equimolecularamounts at a temperature of about '90-100"C. for about 6 hour's,thereafter pouring the reaction mixture into an excess of water, andithereafter saltlng. out the free base.

' 20. A process "for the synthesisof" 3-di'ethylamino-1%lhydroxycyclohexyl) 1 ipro'pancm'e which comprises reactingl'r-h'ydroxycycl'oh'exyl methyl ketone, "formaldehyde, andahydrolyza'ble salt of diethylamine, in substantially equimolecularamounts at a temperature of about -100 C. for about 3, /2 hours,thereafter pouring, the reaction'mixtureinto an excess of water, andthereafter salting out the ,free base. I

,RICHARD WILDER. DANIEL. F. HERMANL REFERENCES CITED The followingreferences are of record -iri :-the file of this patent:

UNITED srATESPATENTS OTHER, REFERENCES Adams. et al.: "OrganicReactions]? v01. 11, DD. 303-341. (John Wiley and Sons, Inc.,-1944);Spaeth etaL: J. Org. Chem., vol. 11,,pp. 399-404 (1946).

1. N-DISUBUTITUTED AMINO-T-HYDROXY KETONES OF THE GENERAL FORMULA